Abdominal adipose tissue inflammation predisposes to insulin resistance and is a leading risk factor for metabolic syndromes, cardiovascular diseases, autoimmune diseases and cancer. Our lab aims to investigate how diet-induced abdominal obesity affects immune regulation, when and how to boost such regulation and reverse obesity-induced inflammatory diseases. Preliminary discovery: Our research team has discovered a new B lymphocyte population inside abdominal cavity and adipose tissue. These cells, termed L2pB1 cells, are the producer of natural anti- phospholipid IgM antibody that attenuates atherosclerosis through inhibiting macrophage from taking in lipids. Strikingly, we found that these L2pB1 cells are also the predominant B cells that express the anti- inflammatory cytokine IL-10 in adipose tissue. More importantly, L2pB1 cells specifically engulf phospholipids- containing particles. Thus, in addition to potential anti-inflammatory regulation through IL-10 production, L2pB1 cells have the cross-lineage phenotypes and functions of both B lymphocytes and macrophages. Most intriguingly, we found that in diet-induced obese mice, IL-10-producing L2pB1 cells are dramatically diminished in abdominal adipose tissue. The specificity of L2pB1 cell phagocytosis towards phospholipids is also disappearing in these obese mice. Hypothesis: We hypothesize that L2pB1 cells may be a unique key immune component to regulate adipose tissue homeostasis and inflammation in ways distinct from macrophages, T cells and conventional B cells. Boosting L2pB1 cell number and functions might be able to reverse abdominal adipose tissue inflammation and prevent downstream metabolic syndromes. Approach: To test this, our research team has generated a novel knock-in animal model, which allows us to track, monitor and quantify L2pB1 cells in real time in obese mice. It also allows inducible depletion of L2pB1 cells at various stages of disease development and will help determine the timing and essential roles of L2pB1 cells. We also propose to isolate L2pB1 cells and perform adoptive transfer to diseased animal to test whether L2pB1 cells isolated from healthy lean donors can reverse adipose tissue inflammation and insulin resistance. In addition, in collaboration with a bioengineering team, we have developed a pH-sensitive nano-particle that can specifically detect and track such phagocytic B lymphocytes in our proposed animal model. This novel nano-technique will potentially be useful to identify and monitor similar B lymphocytes in human patients. We also identified and constructed a fusion cytokine to specifically boost L2pB1 cells. Significance: Our study will provide novel technique and new knowledge of an immune regulation mechanism bridging conventional innate and adaptive immunity. The results will provide better understanding and a more holistic picture of the immune regulation network that protects tissue from DIO-induced damage.